PROJECT SUMMARY/ABSTRACT Doxorubicin (DOX) is a potent chemotherapeutic agent reserved for second line therapy, such as recurrent ovarian cancer, due to its cardiotoxicity and drug resistance issues. With a cumulative lifetime dose limit of 450-550 mg/m2 patients who have benefited from its use before may be barred from further use in any relapses. One promising solution to DOX's cardiotoxicity and chemoresistance is through the use of phytochemicals such as resveratrol (RES), curcumin (CUR), or quercetin (QUE). Although these phytochemicals have been shown to be cardioprotective and can overcome tumor resistance through chemosensitization, they require long pre-treatment times and have short biologic half-lives, restricting their value in addressing DOX's limitations. However, our preliminary in vitro and in vivo research suggests that these phytochemicals, when dosed concurrently in specific combinations in polymeric micelles with existing DOX formulations, are both cardioprotective and chemosensitizing while delivering clinically relevant concentrations of the molecules. The proposed project will extend our preliminary work through two specific aims. Specific Aim 1 will establish preclinical safety and pharmacokinetic profiles for the micellar phytochemicals for use with DOX. Specific Aim 2 will validate the efficacy of the complementary therapeutic approach, i.e., cardioprotection with chemosensitization, in ovarian cancer xenograft mouse models. The significance of the work lies in developing a complementary therapeutic strategy using phytochemicals as a cost-effective strategy to mitigate DOX-induced cardiotoxicity and to chemosensitize resistant cells. By effecting these changes, the cumulative lifetime dose limit of DOX will be increased, making it available for wider applications, including recurrent relapses. Further, these effects will be accomplished without changing the current dosing schedule, increasing the likelihood of patient compliance. The impact of this proposal lies in addressing both mechanisms of DOX-induced cardiotoxicity, ROS and TOPII? inhibition, without compromising DOX efficacy or resulting in additional side effects associated with the complementary approach. The global impact of this project lies in addressing the under-utilization of DOX use through a complementary approach, thus increasing the range of treatment options and ultimately the quality of care for patients. In addition, this approach to developing micellar phytochemicals has significant potential for use with other chemotherapeutic agents for which drug resistance is a concern. This R15 application offers excellent research training opportunities for undergraduate, graduate, and pharmacy students and will make significant contributions to the enhancement of the Pacific University research infrastructure while strengthening Oregon State University's biomedical research.